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Edited by David W. Russell, University of Texas Southwestern Medical Center, Dallas, TX, and approved April 20, 2015 (received for review December 2, 2014)
Significance
Primary and metastatic liver cancers that are associated with high mortality rates and poor treatment responses are only diagnosed at late stages, due to the lack of highly sensitive contrast agents and robust imaging methodologies. We have developed a protein MRI contrast agent (ProCA32) by engineering high-affinity Gd3+-binding pockets in rat and human α-parvalbumin. ProCA32 can function as both a T1- and T2-weighted contrast agent, which enables noninvasive detection of early-stage micrometastatic liver tumors with sizes as small as 0.24 mm using T1- and T2-weighted or T2/T1 ratio MRI. Our protein-based MRI contrast agents and imaging methodology are expected to provide robust results for the early detection of liver cancer as well as other liver diseases.
Abstract
With available MRI techniques, primary and metastatic liver cancers that are associated with high mortality rates and poor treatment responses are only diagnosed at late stages, due to the lack of highly sensitive contrast agents without Gd3+ toxicity. We have developed a protein contrast agent (ProCA32) that exhibits high stability for Gd3+ and a 1011-fold greater selectivity for Gd3+ over Zn2+ compared with existing contrast agents. ProCA32, modified from parvalbumin, possesses high relaxivities (r1/r2: 66.8 mmol−1⋅s−1/89.2 mmol−1⋅s−1 per particle). Using T1- and T2-weighted, as well as T2/T1 ratio imaging, we have achieved, for the first time (to our knowledge), robust MRI detection of early liver metastases as small as ∼0.24 mm in diameter, much smaller than the current detection limit of 10–20 mm. Furthermore, ProCA32 exhibits appropriate in vivo preference for liver sinusoidal spaces and pharmacokinetics for high-quality imaging. ProCA32 will be invaluable for noninvasive early detection of primary and metastatic liver cancers as well as for monitoring treatment and guiding therapeutic interventions, including drug delivery.
Footnotes
- ↵1To whom correspondence should be addressed. Email: jenny{at}gsu.edu.
Author contributions: S.X., X.P.H., H.E.G., Z.-R.L., and J.J.Y. designed research; S.X., H.Y., J.Q., F.P., J.J., K. Hubbard, K. Hekmatyar, J.L., M.S., R.C.L., and R.G.B. performed research; S.X., H.Y., J.L., M.S., X.P.H., H.E.G., and J.J.Y. contributed new reagents/analytic tools; S.X., H.Y., F.P., J.L., R.G.B., X.P.H., H.E.G., Z.-R.L., and J.J.Y. analyzed data; and S.X., R.G.B., Z.-R.L., and J.J.Y. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1423021112/-/DCSupplemental.
Protein MRI contrast agent for cancer imaging
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